Although latency was not statistically different between the groups, MPEP treated Fmr1 KO mice made significantly fewer errors on mazes deemed more difficult suggesting a reversal of the behavioral deficit. MPEP treated mice were also less perseverative and impulsive when navigating mazes. Furthermore, MPEP treatment reversed post-synaptic density-95 (PSD-95) protein deficits in Fmr1 KO treated mice, whereas levels of a control protein (β-tubulin) remained unchanged. These data further validate MPEP as a potentially beneficial treatment for FXS. Our findings also suggest that adapted H-W mazes may be a useful tool to document alterations in behavioral functioning following pharmacological intervention in FXS.



MPEP, a selective non-competitive antagonist of group I metabotropic glutamate receptor subtype 5 (mGluR5), administered at doses ranging from 0.75 to 1 mg/kg, failed to influence the electroconvulsive threshold in mice. However, when administered at higher doses (1.25 and 1.5 mg/kg), it significantly increased the threshold. Moreover, MPEP (applied at its highest subprotective dose of 1 mg/kg) did not affect the protective action of valproate, carbamazepine, diphenylhydantoin and phenobarbital against maximal electroshock-induced seizures in mice. The presented results indicate that mGluR5 antagonists should not be considered as good candidates for add-on therapy of generalized seizures.

In each experiment, one group of mice received spared nerve injury (SNI) surgery to model chronic pain; the other group received a control sham surgery. Both fenobam and MPEP induced preference in the SNI mice, such that SNI mice spent significantly more time in the mGluR5 antagonist-paired chamber compared to a vehicle-paired chamber. No such preference developed for sham mice. Morphine induced preference in male and female mice in both the SNI and sham groups.Glutamate, the major excitatory neurotransmitter in the brain, acts on both ionotropic and metabotropic glutamate receptors. Excessive metabotropic glutamate receptor (mGluR) transmission has been linked to epilepsy, ischemia, pain, anxiety, and depression. Eight subtypes (1-8) and multiple splice variants of the mGluR have been identified and grouped based on their pharmacological properties. Group I mGluRs (subtypes 1 and 5) activate the phosphatidyl inositol pathway, while Group II (2 and 3) and Group III (4, 6, 7 and 8) inhibit adenylyl cyclase. MPEP is a potent, highly selective non-competitive antagonist at the mGlu5a receptor subtype (IC50 = 36 nM) while having no agonist or antagonist activities at the mGlu1b receptor at concentrations up to 30 μM. MPEP is centrally active following systemic administration in vivo, inducing anxiolytic-like effects in rodent models of anxiety and depression when administered at 1-30 mg/kg. MPEP has also been reported as a positive allosteric modulator of mGluR4 at μM concentrations.


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